US11234964B2 - Use of melatonin for the treatment of tumors - Google Patents

Use of melatonin for the treatment of tumors Download PDF

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US11234964B2
US11234964B2 US16/498,825 US201816498825A US11234964B2 US 11234964 B2 US11234964 B2 US 11234964B2 US 201816498825 A US201816498825 A US 201816498825A US 11234964 B2 US11234964 B2 US 11234964B2
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melatonin
tumor
tumors
composition
treatment
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US20210106562A1 (en
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Germaine Escames Rosa
Darío Acuña Castroviejo
Ana GUERRA-LIBRERO RITE
Beatriz Irene FERNÁNDEZ GIL
Javier FLORIDO RUIZ
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Universidad de Granada
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention is comprised generally in the medical and pharmaceutical field.
  • the present invention describes the use of melatonin for the treatment of tumors by means of intratumoral administration.
  • Drug resistance is one of the main limitations in clinical oncology and the cause of relapse in many patients, so the search for new therapeutic targets, as well as the search for drugs enhancing the cytotoxic effects of standard treatments, without enhancing the adverse effects, becomes fundamental.
  • HNSCC head and neck squamous cell carcinoma
  • the three main types of treatments for managing head and neck cancer are radiotherapy, surgery, and chemotherapy.
  • the primary treatments are radiotherapy, surgery, or a combination of both, where chemotherapy is often used as additional or adjuvant treatment.
  • Cisplatin is used, and in more resistant cases cetuximab.
  • the optimal combination of the three forms of treatment for a patient with head and neck cancer depends on the site and stage of the disease. There are some new treatments, as well as new combinations of old treatments. A good example of the latter is the use in recent years of a combination of radiotherapy and chemotherapy or immunotherapy for the treatment of advanced head and neck cancer. However, these treatments exhibit a high degree of toxicity in healthy cells. Chemotherapy and radiotherapy treatment is associated with short- and long-term side effects.
  • Melatonin N-acetyl-5-methoxytryptamine
  • melatonin N-acetyl-5-methoxytryptamine
  • Melatonin is a powerful antioxidant which, in addition to scavenging free radicals, increases the expression and activity of endogenous antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GRd), and ⁇ -glutamyl-cysteine synthetase. Furthermore, as it eliminates free radicals, melatonin generates a series of metabolites which are also free radical scavengers that are as powerful as melatonin itself (Urata, Y et al. Free Radio Biol Med 1999, 27, 838-847). In other words, melatonin is more effective than other antioxidants in preventing damage caused by oxidative stress.
  • SOD superoxide dismutase
  • GPx glutathione peroxidase
  • GRd glutathione reductase
  • melatonin goes through all the membranes, reaching all cellular compartments, including the mitochondrion where it is capable of maintaining mitochondrial homeostasis in different experimental models (Acuna-Castroviejo et al. Cell Mol Life Sci 2014, 71, 2997-3025; Diaz-Casado et al. J Pineal Res 2016, 61, 96-107; Doerrier et al. Mitochondrion 2016, 27, 56-63). Melatonin increases membrane fluidity, electron transport chain (ETC) complex activity, ATP production, and mitochondrial membrane potential, while reduces oxidative stress and mitochondrial permeability transition pore closure.
  • ETC electron transport chain
  • melatonin protects normal cells from apoptosis while at the same time increases apoptotic cell death in several types of cancerous cells (Trubiani et al. J Pineal Res 2005, 39, 425-431). Its immunomodulating anticarcinogenic action also increases anti-tumor immune response (Miller et al. Int J Exp Pathol 2006, 87, 81-87). Furthermore, melatonin has a significant metabolic effect as it reduces glucose intake by cancerous cells, and accordingly inhibits tumor growth through the suppression of linoleic acid absorption and the metabolism thereof by the tumor to produce the mitogenic molecule 13-NODE (Blask et al. Cancer Res 1999, 59, 4693-4701).
  • the intratumoral injection of ethanol is a simple and cost-effective technique used in the treatment of hepatocarcinomas, particularly encapsulated hepatocarcinomas.
  • melatonin inhibits cell proliferation and increases cell death provided that suitable amounts of same enter the tumor cell
  • the use of melatonin such that it allows reducing recurrences in cancer treatment, as well as resistance to oncostatic treatments, has not been described up until now.
  • the present invention relates to a pharmaceutical composition for intratumoral administration comprising high concentrations of melatonin, melatonin derivatives, or metabolites, such that the melatonin exerts an oxidizing effect, in contrast to the regular use thereof, and particularly to the use thereof proposed, for example, in [U.S. Pat. No. 9,289,428 B2]. It increases mitochondrial function, and accordingly the production of free radicals activating cell death.
  • FIG. 1 Analysis of melatonin penetration in tumor cells. It is observed that melatonin readily enters the tumor cells in a dose-dependent manner in the in-vitro experiments. It reaches maximum levels of 450 ng/mg of proteins after incubating the cells with melatonin at a dose of 1500 ⁇ M for 24 hours.
  • FIG. 6 Mitochondria and cristae analysis. It is observed that melatonin increases the number of mitochondria as well as the number of cristae ( FIG. 6A ). It also increases mitochondrial DNA ( FIG. 6B ) and mitochondrial mass ( FIG. 6C ). The result is an increase in respiratory chain complexes, and accordingly an increase in oxygen consumption ( 6 D), which is related to an increase in free radicals ( 6 E) and oxidative stress. This increase in free radicals induces cell death in tumor cells.
  • compositions of the invention are suitable for the treatment of malignant tumors, preferably tumors associated with head and neck cancer, melanoma, breast tumors or breast cancer-associated tumors, ocular tumors, urologic tumors, such as testicular tumors, and hepatic tumors, such as hepatocarcinoma, cervical tumors, lymphomas, thyroid tumors, soft part sarcoma.
  • malignant tumors preferably tumors associated with head and neck cancer, melanoma, breast tumors or breast cancer-associated tumors, ocular tumors, urologic tumors, such as testicular tumors, and hepatic tumors, such as hepatocarcinoma, cervical tumors, lymphomas, thyroid tumors, soft part sarcoma.
  • the amount of compound X, metabolite, salt, solvate, or prodrug constituting a therapeutically effective amount will vary, for example, according to the activity of the specific compound used; the metabolic stability and the duration of action of the compound; the species (preferably human), the type of tumor, the age, body weight, general condition of health, sex, and diet of the patient, the route of administration, the mode and time of administration, the excretion speed, the combination of drugs, the severity of the particular disorder or pathological condition, and the subject who is subjected to therapy, but it can be determined by one skilled in the art according to their knowledge and that description.
  • the concentration which gives rise to the therapeutically effective amount of the compound of formula X, preferably melatonin is greater than 0.1% (w/v) with respect to the total composition being administered.
  • this concentration is greater than 0.2% (w/v), more preferably greater than 0.3% (w/v), even more preferably it is comprised between 0.3 and 5% (w/v), and even more preferably between 0.3 and 4.5% (w/v).
  • the concentration of the compound of formula X, preferably melatonin, which gives rise to the therapeutically effective amount is greater than 0.1% (w/v) with respect to the total composition being administered, preferably greater than 0.2% (w/v), more preferably it is comprised between 0.2% and 0.5%, and still more preferably it is 0.3% (w/v).
  • composition of the invention comprises melatonin with a concentration of at least 0.16 million times greater.
  • Said formulations can contain any other active ingredient in the treatment of tumors or can be characterized by containing, as an active ingredient, only a compound of general formula X or a combination of compounds of general formula X.
  • composition further comprises at least another active ingredient.
  • active principle refers to any component which potentially provides a pharmacological activity or another different effect in the diagnosis, cure, mitigation, treatment, or prevention of a disease, or which affects the structure or function of the body of human beings or other animals.
  • other oncostatic molecules can be used.
  • the formulations can furthermore contain pharmaceutically acceptable excipients or adjuvants.
  • excipients and vehicles used must be pharmaceutically and pharmacologically tolerable, such that they can be combined with other components of the formulation or preparation and do not exert adverse effects in the treated organism.
  • the best dosage form will depend on the type of tumor and on the condition of the patient.
  • an example of pharmaceutically acceptable vehicle is 10% propylene glycol (PG) and isotonic saline solution.
  • compositions or formulations must be suitable for intratumoral administration by means of injection, electroporation or electropermeabilization, ultrasound-mediated administration, creams, lotions, or other dosage forms.
  • adjuvant refers to any substance which enhances the response of an active ingredient. In the present invention, it refers to any substance which enhances the effects of the composition of the invention, and it can refer to any adjuvant known by one skilled in the art.
  • pharmaceutically acceptable refers to the fact that the compound to which reference is made is allowed and evaluated such that it does not cause any damage to the organisms to which it is administered.
  • composition further comprises a gelling agent.
  • the gelling agent is selected from the list comprising polyethylene and polypropylene copolymer, cellulose, and guar gum.
  • it relates to polyethylene and polypropylene copolymer.
  • another preferred embodiment relates to the use in which the composition is a gel (or also referred to as “hydrogel”).
  • an example of pharmaceutically acceptable vehicle is a 5% isotonic pluronic solution.
  • gelling agent refers to a substance forming a gel, i.e., a three-dimensional network formed by the gelling agent and generally containing a liquid phase.
  • the gelling agents which can be used for manufacturing the gel which is administered intratumorally can be those known by one skilled in the art for the elaboration of a pharmaceutical composition.
  • poloxamer copolymers for example the agents referred to as Pluronic® including, among others, Pluronic® F127 (CAS number 9003-11-6) or Pluronic® F127NF, can be used.
  • composition further comprises at least one preservative.
  • Preservative is understood to be that substance which maintains the properties of the medicinal product by inhibiting contamination by germs, and they can be ionic or non-ionic preservatives.
  • the preservative used must not be toxic, must be chemically stable and compatible with melatonin.
  • Those preservatives known in the state of the art can be used as preservative agents, for example, the preservative can refer to benzoic acid, sodium benzoate, ascorbic acid, potassium sorbate, methylparaben, ethylparaben, or butylparaben.
  • “Germs” is understood to be any cell that can grow and multiply in the composition of the invention, for example bacteria, fungi, and yeasts.
  • the amounts of active substances to be administered can vary depending on the particularities of the therapy.
  • compositions of the invention are prepared using standard methods such as those described or referred to in the Spanish and United States Pharmacopoeias and similar reference texts.
  • compositions, preparation, or dosage form suitable for intratumoral administration hereinafter “combined preparation of the invention,” comprising:
  • kit refers to a combination of a set of components which are suitable for obtaining the composition or the combined preparation of the invention, may or may not be packaged together, along with their containers and packaging suitable for marketing, etc.
  • component suitable for obtaining the composition or the combined preparation of the invention is understood to be any compound which can be used for obtaining same and includes, without limitation, aqueous solutions, solid preparations, buffers, syrups, preservation solutions, flavoring agents, pH correctors, thickeners, etc.
  • kit of parts can be provided in separate vials (in the form of “kit of parts”) or in a single vial.
  • the kit of the present invention is understood to as being intended for the preparation of the composition or the combined preparation or the dosage form of the invention.
  • the components of the kit of the present invention are ready-to-use components for preparing the composition or the combined preparation or the dosage form of the present invention.
  • the kit preferably contains instructions explaining how to prepare the composition or the combined preparation or the dosage form of the present invention. The instructions can be provided to users in electronic or printed format.
  • the invention provides a kit for the preparation of the composition of the invention or the combined preparation of the invention, a container comprising a receptacle with the compound of general formula X in any pharmaceutically acceptable formulation, together with components suitable for obtaining the composition or the combined preparation of the invention.
  • the kit of the invention further comprises a receptacle with the compound of general formula X in any pharmaceutically acceptable formulation.
  • a third aspect of the invention consists of the use of a compound of general formula X, a salt, a solvate, or a prodrug thereof for the preparation of a pharmaceutical composition for the treatment of a tumor, in which the pharmaceutical composition is administered intratumorally.
  • the administered amount depends on tumor size and localization.
  • melatonin increases the levels of free radicals in the cell.
  • Melatonin increases the number of mitochondria as well as the number of cristae, DNA, and mitochondrial mass.
  • the result is an increase in respiratory chain complexes, and accordingly an increase in oxygen consumption, which is related to an increase in free radicals and oxidative stress reflected by an increase in the GSSG/GSH ratio.
  • the antioxidant capacity is not modified.
  • the activity and the expression of antioxidant enzymes such as GPx and the GRd is not modified either.
  • a slight increase in SOD is observed.
  • SCC-9 cells that are more resistant to melatonin, exhibit less mitochondrial changes with melatonin, and accordingly less production of reactive oxygen species (ROS).
  • ROS reactive oxygen species
  • CAL-27 and SCC9 cells have been used as typical example of head and neck squamous cell carcinoma (HNSCC) cancer cells.
  • HNSCC head and neck squamous cell carcinoma
  • Athymic nude mice (nu/nu) (Janvier, Pays de la Loire, France) of about 5-6 weeks of age (18-20 g) were used.
  • the animals were held in the animal housing unit of the Biomedical Research Center of University of Granada (CIBM) in sterile conditions and under controlled photoperiod (12:12 h) and temperature (22 ⁇ 1° C.) environments, with ad libitum water and laboratory diet.
  • the handling and transplant of the animals was carried out in a laminar flow biosafety cabinet.
  • the animals were anesthetized with an i.p. injection of ketamine (80 mg/kg) and xylazine (4 mg/kg).
  • Xenografts were performed with CAL-27 and SCC9 cells (the latter being resistant to melatonin). Cells enzymatically separated with trypsin-EDTA are resuspended at a concentration of 4 ⁇ 10 6 cells per mouse in PBS. Cell viability is determined by means of the Trypan Blue test. The cells are injected into the left flank of the mouse, with a volume of 200 ⁇ L of cell suspension being injected into each mouse with the help of a 1 mL syringe with a needle measuring 16 ⁇ 0.5 mm.
  • the body weight and tumor size are measured and recorded two or three times a week throughout the experiment.
  • the tumor volume is calculated using the following formula: 1 ⁇ 2 (L ⁇ W2) (mm 3 ), where L is the length and W is the width.
  • 4.5% melatonin is the maximum dose used s.c. in vivo.
  • the tumor cells were incubated with different concentrations of melatonin. It was observed that melatonin readily enters the tumor cells, reaching levels of 450 ng/mg of proteins after incubating the cells with melatonin at a dose of 1500 ⁇ M for 24 hours ( FIG. 1 ).
  • melatonin activates the apoptotic mechanisms in tumor cells by acting on the mitochondria of said cells, in addition to enhancing the cytotoxic effects of radiotherapy and chemotherapy.
  • a significant decrease has been observed in the size and number of colonies of tumor cells (CAL-27) irradiated and treated with melatonin.
  • Melatonin increases apoptosis in a dose and time dependent manner. Inhibition of cell proliferation and stopping of cell cycle in the S and G2 phases have also been observed.
  • the relationship between the mitochondrial changes caused by melatonin and the cell death induced by this molecule in these tumor cells has been studied.
  • Melatonin increases mitochondrial mass, mitochondrial DNA, the number of mitochondria, as well as the number of mitochondrial cristae. The result is an increase in respiratory chain complexes, and accordingly an increase in oxygen consumption, which is related to an increase in free radicals and oxidative stress. Furthermore, it is observed that melatonin does not increase the activity of antioxidant enzymes such as GPx or GRd, which leads to an even greater production of free radicals. In other words, the cytotoxic effects of melatonin in the tumor cells are related to an increase in mitochondrial function, and the increase in mitochondrial function in the tumor cell in turn induces apoptosis processes, which also entails the inhibition of protein synthesis.
  • SCC-9 head and neck cancer cells are more resistant to melatonin, with less effect on mitochondrial function, and therefore a lower production of free radicals, being observed at the same time. These results indicate that melatonin enters these cells at lower concentration.
  • melatonin was administered subcutaneously at a dose of 300 mg/kg.
  • the amount of melatonin entering the tumor is negligible (14 ng/mg of proteins) despite the administration of a melatonin dose of 300 mg/kg of weight of the mouse ( FIG. 2 ), which indicates that there is a certain mechanism which prevents the entry of sufficient amounts of melatonin to exert its effects in the tumor cell.
  • the concentration of melatonin in the tumors was measured after sacrificing the animals after 21 days. When it is injected directly into the tumor, the concentration of melatonin cannot be measured due to the limited amount of sample taking into account that the tumor practically disappears.
  • the tumor volume decreases very little with respect to the control ( FIG. 3 ). Neither increasing the dose of melatonin above 300 mg/kg of weight, nor increasing the days of treatment, allows observing an increase in the effect of melatonin on the tumor. In other words, melatonin does not enter the tumor in a higher amount. However, the tumor volume decreases drastically 21 days after treatment when melatonin is injected directly into the tumor (intratumoral injection), and completely disappears 28 days after treatment.

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ES201730598A ES2684408B1 (es) 2017-03-31 2017-03-31 Uso de melatonina para el tratamiento de tumores
ESP201730598 2017-03-31
ESES201730598 2017-03-31
PCT/ES2018/070289 WO2018178497A2 (es) 2017-03-31 2018-04-02 Uso de melatonina para el tratamiento de tumores

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US10092544B2 (en) * 2012-11-28 2018-10-09 Universidad De Granada Composition comprising melatonin or its derivatives with coenzyme Q10 and use thereof against ageing of the skin

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EP3603635A2 (en) 2020-02-05
US20210106562A1 (en) 2021-04-15
EP3603635A4 (en) 2021-01-20
WO2018178497A3 (es) 2018-11-15
WO2018178497A2 (es) 2018-10-04
BR112019020519A2 (pt) 2020-05-05
ES2684408B1 (es) 2019-07-09

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